Journal article
Inactivation of Cancer-Associated-Fibroblasts Disrupts Oncogenic Signaling in Pancreatic Cancer Cells and Promotes Its Regression
Cancer research (Chicago, Ill.), Vol.78(5), pp.1321-1333
03/01/2018
DOI: 10.1158/0008-5472.CAN-17-2320
PMID: 29259015
Abstract
Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) that stimulate oncogenic signaling in TEC. In this study, we evaluated the cross-talk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mut p53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGF beta signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, nonproliferative state. TEC exposed to media conditioned by drug-treated CAFs exhibited a decrease in oncogenic signaling, as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGF beta. Given promising early clinical studies with Minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma cross-talk may offer a viable strategy to treat pancreatic cancer.
Significance: In an established mouse model of pancreatic cancer, administration of the promising experimental drug Minnelide was found to actively deplete reactive stromalfibroblasts and to trigger tumor regression, with implications for stromal-based strategies to attack this disease. (C) 2018 AACR.
Details
- Title: Subtitle
- Inactivation of Cancer-Associated-Fibroblasts Disrupts Oncogenic Signaling in Pancreatic Cancer Cells and Promotes Its Regression
- Creators
- Patricia Dauer - University of MinnesotaXianda Zhao - University of MinnesotaVineet K. Gupta - University of MiamiNikita Sharma - University of MiamiKousik Kesh - University of MiamiPrisca Gnamlin - University of MiamiVikas Dudeja - University of MiamiSelwyn M. Vickers - University of MinnesotaSulagna Banerjee - University of MiamiAshok Saluja - University of Miami
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.78(5), pp.1321-1333
- DOI
- 10.1158/0008-5472.CAN-17-2320
- PMID
- 29259015
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 13
- Grant note
- Katherine and Robert Goodale foundation R01CA124723 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Minneamrita Therapeutics LLC R01-CA170946; CA124723; R01-CA184274 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 03/01/2018
- Academic Unit
- Anatomy and Cell Biology; Surgery
- Record Identifier
- 9985244678502771
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